DESCRIPTION Alcohol abuse is one of the most devastating and costly diseases. Its mechanisms are not well understood and effective treatment is lacking. One way to study this complex disease is with the use of model organisms. Zebra fish (Danio rerio) may be a useful model system with which the mechanisms of acute and chronic effects of alcohol can be investigated. However, high throughput behavioral tests allowing fast screening of alcohol related functional alterations of the brain of zebra fish (or tests allowing quick detection of neurobiological changes induced by mutations of genes associated with alcohol related mechanisms) are almost completely unavailable. The goal of the proposal is to develop such behavioral paradigms. A novel Y-tank system will be designed in which zebra fish will swim against a slow water current and choose between the left or right goal arms of the tank. The paradigm is versatile and will enable us to test motor function, alcohol preference/avoidance, and alcohol rewarded place preference. Quantification of behavior hi the test will be automated with the use of infrared photocell detectors feeding the behavioral data to computers that will monitor and record the behavioral responses as well as control the delivery of stimuli (e.g., alcohol and conditioned stimuli). Automation will allow us to increase the number of apparati running in parallel thus making the system useful for high throughput screening. Ultimately, we will use the paradigm to screen and identify mutant zebra fish generated by random mutagenesis (ethyl-nitroso-urea or ENU induced point mutations), a forward genetic approach that will lead to the identification of genes involved in acute and chronic alcohol related behaviors. Zebra fish is particularly appropriate as a model organism for our purpose because of its small size, prolific nature (200+ fish per spawning), ease of controlling of its environment, ease of delivery of water soluble substances such as alcohol (fish absorb it through their gills and skin), and the huge amount of genetic information and genetic tools available. As several genes discovered in zebra fish show high homology to human, we hope the proposed studies will facilitate the unraveling of the mechanisms of acute and chronic alcohol effects in human ultimately resulting in the development of efficient treatments.